Eve A. Roberts, M.D., FRCPC
Division of Gastroenterology and Nutrition, Department of Pediatrics,
The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada

What is Wilson disease?

Wilson disease (technical name: hepatolenticular degeneration) is an inherited disorder
of copper handling in the liver. Copper is not packaged properly into its carrier
protein in the liver, and it is not excreted efficiently into the bile. Consequently,
copper accumulates in liver cells. When too much copper is in liver cells, it spills
into the blood stream and is deposited in other organs, mainly the brain and the
eyes.

Where does the copper come from?

Copper is found in many foods. Trace amounts are essential for good health, but
too much copper can be toxic. Most people excrete the extra copper that they do
not need, but persons with Wilson disease cannot do this adequately.

If it is a copper disorder, why is it called Wilson disease?

Wilson disease is named after an eminent neurologist, Kinnear Wilson, who first
described the disease in 1912. Although born in the United States, he worked mainly
in England. He described progressive neurologic disease in children in the same
family, although he observed that some children also had liver disease. The ring
of copper deposited in the eye, near the iris, called the Kayser-Fleischer ring,
was described only a few years earlier. Copper's role in damaging the liver was
confirmed in the late 1940s. The genetic pattern of inheritance (called autosomal
recessive) was determined in 1960. The gene that is abnormal in Wilson disease was
identified in 1993. The technical name for this gene is ATP7B, but it also
is called WND. The gene is located on chromosome 13.

What kind of gene is abnormal in Wilson disease?

The gene that is abnormal in Wilson disease (ATP7B) is the blueprint for
a protein found mainly in liver cells but also in some brain cells and in certain
parts of the kidney. In liver cells, this protein uses energy stored in the cell
to move copper out of the cell, which is why the protein is called a "copper-transporter."
If the gene is abnormal, then the protein is not put together correctly and does
not work.

What is known about the gene?

The gene is large, with over 80,000 base pairs organized in 22 coding units. By
looking at the patterns in the gene, scientists can predict the features of the
protein it makes. The protein has a tail of 6 units to bind copper and a zone to
make a hole, or "pore" in a membrane, through which copper moves; it also has the
mechanism for capturing cellular energy to fuel the whole process of transporting
copper. This gene is complicated. Thus far, approximately 200 different mutations
(or abnormal changes) in this gene have been identified.

How is Wilson disease inherited?

Autosomal recessive inheritance means that a person must have 2 abnormal versions
of the WND gene to get the disease. The change that makes a gene abnormal
is called a "mutation." In Wilson disease, some people have 2 copies of the same
mutation, but many people with Wilson disease have 1 copy of 2 different mutations.
Either way, having 2 abnormal WND genes means a person has Wilson disease.
If a person has only 1 abnormal gene, then that person is a carrier of the disease
but does not get the disease. The parents of a person with Wilson disease are obliged
to be carriers.

Does Wilson disease occur more often in some populations than in
others?

Wilson disease is considered to be rare. It occurs worldwide at the rate of 1 per
30,000 population, meaning that the carrier rate is approximately 1 per 90 population,
which is a relatively high rate compared to many inherited diseases. Wilson disease
is found in all racial groups. In a few places, the rate of Wilson disease is unusually
high; for example, in Sardinia off the coast of Italy, the disease rate is approximately
1 per 10,000 population.

What kind of disease occurs with Wilson disease?

Younger patients typically have signs of liver disease, and the liver disease can
be highly variable. Many adult patients primarily have neurologic disease, usually
with problems relating to movement. These patients usually have signs of liver damage.
Some children and teenagers mainly develop neurologic disease. A minority of patients
has only psychiatric symptoms. Although copper can be deposited in the eye, it does
not disturb eyesight.

When does the disease begin?

Since Wilson disease is genetic, it is with a person from birth. Most people remain
asymptomatic for years and do not know that they have Wilson disease. Children as
young as 3 years can have severe liver disease from Wilson disease. Some adults
develop only neurologic problems due to Wilson disease when they are in their fifth
decade. In general, liver problems from Wilson disease become evident in people
aged 5 through 40 years. Those persons with neurologic problems from Wilson disease
become symptomatic when they are aged 10 through 55 years.

What kind of liver disease occurs with Wilson disease?

One of the complicated aspects about Wilson disease is that it leads to many different
types of liver disease some severe, some not. At an early stage, Wilson disease
may cause slight enlargement of the liver, possibly with extra fat in the hepatocytes.
At a later stage, the liver becomes scarred or cirrhotic, often without any symptoms
of liver disease. Patients with clinically evident liver disease can have an acute
illness similar to viral hepatitis or resembling an autoimmune liver injury. Exceptionally,
sudden and rapidly progressive liver failure can occur. This usually is accompanied
by an abrupt and severe anemia, poor clotting function, changes in mental function
(eg, stupor, coma), and renal failure.

What neurologic problems occur with Wilson disease?

Symptoms of Wilson disease affecting the nervous system are extremely variable,
but with 2 main patterns. Movement disorders include tremors, involuntary movements,
poor coordination, and loss of fine movements. Many patients actually have decreased
movement; they get a stiffness of movement, mincing pattern to their gait, and loss
of relaxed and spontaneous facial expression. They also may have garbled speech,
drooling, and difficulty swallowing. In teenagers, excessive clumsiness, unexplained
deterioration in school performance, and change in handwriting from large round
letters to small jagged letters warrant consideration of Wilson disease. Personality
or mood changes or depression may accompany these symptoms. Seizures are uncommon
with Wilson disease. Intellect is normal.

Can Wilson disease affect other organs?

Copper can accumulate in the heart muscle and result in an abnormal heart rhythm.
Copper overload in the pancreas can cause pancreatitis. Copper can cause red blood
cells to break down (hemolytic anemia), leading to some jaundice. Gallstones also
may result. Copper can interfere with various endocrine organs. In particular, women
with Wilson disease may have difficulty becoming pregnant or have repeated miscarriages.

How is Wilson disease diagnosed?

Relatively simple blood and urine tests may be enough to determine whether or not
a person has Wilson disease. The concentrations of copper and ceruloplasmin in the
blood are low. The amount of copper excreted in the urine over 24 hours is higher
than normal. Blood tests to determine liver function are performed. A computed tomography
(CT) scan or magnetic resonance imaging (MRI) of the brain may be performed. The
eyes should be examined carefully with a slit lamp to see if early Kayser-Fleischer
rings are present. More complicated tests include sampling a small amount of the
liver by a liver biopsy to examine the liver under the microscope and to measure
the actual amount of copper in the liver tissue. Genetic testing can be performed
with a blood sample to determine gene patterns that go with Wilson disease or to
detect specific mutations.

Can Wilson disease be treated?

Wilson disease was one of the first liver diseases for which effective, lifesaving
treatment was found. Currently, several possible treatments are available for Wilson
disease. These treatments are the chelators, penicillamine and trientine, and the
metallothionein-inducer, zinc. Other treatments are essentially experimental.

What is penicillamine and what does it do?

In use since 1956, penicillamine is a treatment for Wilson disease. It binds copper
and increases the excretion of copper in the urine. This treatment may increase
the amount of the safe storage protein for copper, called metallothionein, in liver
cells. Penicillamine has other unrelated actions that include inhibiting the immune
response and interfering with the formation of collagen (a protein in fibrous tissues).
Although originally identified as a breakdown product of the antibiotic penicillin,
this drug currently is manufactured by itself, without involving penicillin. Penicillamine
may deplete vitamin B6 (pyridoxine) in the body; therefore, extra vitamin
B6 is taken with it.

Is penicillamine a good treatment for Wilson disease?

Penicillamine has been a lifesaving treatment for Wilson disease since it first
was discovered, and many specialists still regard it as the first-line treatment
for Wilson disease. Although this treatment works for most people, it can have adverse
effects, including fever and rash soon after starting the drug, damage to the kidneys
causing protein to leak into the urine, problems with the bone marrow so that blood
counts drop dangerously low, and complicated damage to numerous organs at the same
time (ie, "lupus-like" drug reaction). Some patients who mainly have neurologic
problems with Wilson disease get worse neurologically soon after starting penicillamine;
this problem is usually, though not always, transient. A patient having any of these
adverse effects may need to change to another treatment. The blood count and urinalysis
have to be monitored whenever penicillamine is used. Some specialists believe that
penicillamine is flawed as a treatment because of the potential for these adverse
effects and advocate using other treatments.

What are the other treatments?

Trientine is a very different chemical from penicillamine, but it is also capable
of binding copper and of increasing the amount of copper excreted in the urine.
This treatment does not have the risk for adverse effects like penicillamine. When
trientine is substituted for penicillamine, the adverse effects of penicillamine
usually stop. Anemia may develop because this drug also can bind iron, and, rarely,
it may cause nausea because of stomach irritation. Trientine is not quite as strong
a binder of copper as penicillamine, but, in day-to-day experience, this difference
is not important. Zinc, taken in very high doses, removes copper from the body by
increasing the amount of metallothionein in the cells lining the intestinal tract.
Copper is bound within these cells and lost in the feces as these cells turn over
every 3-5 days. Zinc is surprisingly strong and quite specific for eliminating copper
from the body. This treatment has few adverse effects, but it can cause stomach
irritation (gastritis).

Are these the only treatments?

A few other copper-binding agents have been tried and largely discarded from general
use because they were unpleasant to take (eg, daily injections) or had unacceptable
adverse effects. Some agents are still under development (eg, tetrathiomolybdate),
which means that their effectiveness and adverse effects are not yet fully known.
The safety and effectiveness of combining treatments also is not fully determined.

Is treatment lifelong or can it be stopped at some point?

Most people can be treated satisfactorily with the currently available treatments
(ie, penicillamine, trientine, zinc). Any of these treatments must be used daily
for life. If a treatment has to be stopped because it is causing an adverse effect,
another treatment must be substituted. Stopping successful treatment altogether
inevitably leads to major deterioration. If treatment is started again, it may not
work. In most cases, liver transplant then becomes the only effective treatment
available.

How should treatment be monitored?

Most patients have follow-up visits twice a year to ensure that they are generally
healthy. Their physician conducts a physical examination and monitors for adverse
effects of drug treatment. Blood counts, liver tests, and urinalysis are performed,
and the level of copper and ceruloplasmin in the blood is checked. The amount of
copper excreted in the urine in 24 hours is checked approximately once a year to
ensure that treatment is effective. A follow-up slit lamp examination of the eyes
may be performed to see whether the Kayser-Fleischer rings disappear.

Is a special diet necessary?

Especially in the first year of treatment, foods that have very high concentrations
of copper should be avoided. These foods are shellfish, nuts, chocolate, mushrooms,
and organ meats (eg, brains, liver). Since the latter do not play an important role
in the average North American diet, shellfish, nuts, and chocolate are the foods
to target. Advice from a dietitian may be helpful and is mandatory for practicing
vegetarians. Well water or water brought into the household through copper pipes
should be checked for copper content. In general, municipal water supplies do not
have to be checked. A water purifying system may be advisable if the copper content
of the water is high.

Are there any other treatment strategies?

Copper may damage liver cells and other cells in the body by causing the formation
of activated chemical intermediates. Antioxidants, such as vitamin E, may neutralize
these chemicals. High doses of vitamin E may be used in addition to a drug to bind
copper.

What about liver transplantation for Wilson disease?

Most patients with Wilson disease can be treated successfully just with medication,
and liver transplant is not necessary. A few patients who do not respond to treatment
require a liver transplant. The rare patient whose first sign of Wilson disease
is acute liver failure requires immediate liver transplantation. Some patients on
treatment who have very severe neurologic disease improve if they undergo a liver
transplant, but, presently, the use of liver transplantation to treat the neurologic
disease remains controversial. Patients who fail to comply with medical therapy
may develop overwhelming liver damage, which can be treated adequately only by a
liver transplant.

Is it okay to drink alcohol if a person has Wilson disease?

If a person has Wilson disease and gets pregnant, what should that
person do about medication during the pregnancy?

Although a small risk exists that the medication for Wilson disease will damage
the baby, the greatest risk to the baby occurs if the disease is not well controlled
during pregnancy. Therefore, taking the medication during pregnancy is important
for those women with Wilson disease. Management of the pregnancy by a high-risk
obstetrics team may be advisable depending on the severity of the underlying liver
disease.

If a person has Wilson disease, will that person's children get
it?

Since Wilson disease is inherited by an autosomal recessive pattern, a person must
have 2 abnormal genes to get Wilson disease. This means that if a person with abnormal
genes marries a person with normal genes, the children inherit 1 abnormal gene and
1 of the mate's normal genes. The children are carriers of the disease, but they
do not have Wilson disease. If a person with normal genes marries a person who is
a carrier of Wilson disease (ie, has 1 abnormal gene), then a 50-50 chance exists
with each pregnancy that the child will have Wilson disease.

Since it is a genetic disease, what about family studies?

As soon as 1 child in the family is diagnosed with Wilson disease, all brothers
and sisters should be tested. Each child has a 1 in 4 chance of being affected with
the disease. Initial studies can be limited to a physical examination; blood tests
of liver function; the concentration of copper and its carrier protein, ceruloplasmin,
in the serum; and a measurement of the amount of copper excreted in the urine over
a 24-hour period. If these studies are suggestive of Wilson disease, further studies
may be required. Such studies may include a slit lamp examination of the eyes for
Kayser-Fleischer rings, a liver biopsy, and CT scan or MRI of the brain. Since patients
who begin treatment before they have any symptoms have the best prognosis, performing
these studies is important. If the tests are inconclusive, they should be repeated
several times, at 6- to 12-month intervals. If genetic testing is available, an
excellent alternate approach is to use genetic testing to confirm who is affected
and who is not. The genetic findings in the child with Wilson disease and parents
can be used to guide the studies in the other children. Although a genetic approach
provides the best data, because so many different mutations exist, it may be difficult
to identify which mutation(s) are present in an individual family.

What research is being done?

Research is aimed at understanding as much as possible about the protein that is
coded for by the ATP7B gene. Research is ongoing to identify as many mutations
of the ATP7B gene as possible and to understand why Wilson disease is so
variable as a clinical disease. Research also is focused on learning exactly how
copper damages the liver and other organs so that even safer and more effective
treatments for Wilson disease can be found. Because other inherited diseases involving
copper overload occur, some researchers are studying the basis of those diseases.

Guide to technical words

Hepatolenticular degeneration: The scientific name for Wilson disease, without
using the name of the physician who discovered it, meaning that the main damage
is to the liver and to the lenticular area of the brain Ceruloplasmin: The
protein in the blood that carries over 95% of the copper in the blood stream Metallothionein:
A storage protein for copper and other metals inside of cells Chelator: Any
chemical that binds a metal such as copper Mutation: A change in a gene leading
to the abnormal function of the protein for which the gene codes Kayser-Fleischer
ring: Deposit of copper in the eye, close to the iris; characteristic of
Wilson disease but also found in other conditions with copper overload

Dr. Roberts obtained her medical degree
from the Johns Hopkins University School of Medicine and trained in hepatology at
The Royal Free Hospital under Professor Dame Sheila Sherlock. She is currently professor
of paediatrics, medicine, and pharmacology at the University of Toronto and a hepatologist
at the Hospital for Sick Children.